Interesting findings have emerged from our studies this year. First, we began to tackle the problem of ill-defined phenotypes then we examined the contribution of several potentially functional variants in the gene catechol-o-methyltransferase (COMT) and haplotypes to the risk of schizophrenia (SCZ). Imaging genetics allowed us to evaluate the functional impact of these haplotypes on a neural system-level intermediate phenotype in normals during a working memory (WM) task. Our data shows that complex genetic variation can be validated functionally in humans and linked to prefrontal inefficiency. In a recent review looking at subtle gene effects which may be invisible through traditional clinical and psychometric measures, imaging-genetics has elucidated the contribution of COMT, GRM3, G72, DISC1, and BDNF to cognitive deficits in SCZ. These data suggest that there are common mechanisms underlying susceptibility for SCZ associated with complex genetic variations. Our study which explored the effects a genetic variation in the brain-derived necrotrophic factor (BDNF) gene on hippocampal (HP) gray matter volume found bilateral reductions of HP gray matter volumes in methionine carriers (met) compared with valine carriers (val) subjects. The met-BDNF carriers exhibited additional reduced gray matter volumes predominately in the lateral portion of the frontal lobes. These findings are consistent with the cellular and clinical effects of the BDNF val to met polymorphism and suggest that this change of an amino acid also affects the anatomy of the HP and prefrontal cortex (PFC), identifying a genetic mechanism of variation in brain form and structure related to learning and memory. In another study, which explored the effects of a functional polymorphism in a regulatory region of the human serotonin transporter gene, we found that s-carriers (short protein-carriers), had significantly reduced bilateral gray matter volumes in both the amygdala and the subgenual anterior cingulate. We also found that the serotonin s-allele effect on subgenual cingulate volume is dramatically reduced in met-BDNF allele carriers in comparison to val/val-BDNF carriers. Together, these results suggest that the val to met BDNF polymorphism may be a modifying genetic factor for depression, because it affects development and plasticity of critical brain systems involving serotonin related to the experience of negative mood and may lead, together with abnormal serotonin function (s-allele), to an anatomical substrate reflecting an increased vulnerability for depression.[unreadable] [unreadable] We have assembled DNA plates for analyses of candidate psychiatric susceptibility genes using neuroimaging as a functional validation strategy. We have over 650 normal subjects with high quality imaging data, both functional and structural, with which to explore genetic mechanisms of association. Abnormalities in dopamine (DA) neurotransmission contribute to a broad range of psychiatric disorders, like SCZ. DA plays a critical role in hippocampal processing, which is implicated in emotion regulation. This study examined genotype effect of COMT Val158Met on corticolimbic circuitry and functional connectivity during processing of salient stimuli and the relationship to novelty seeking. Using fMRI we found that the Met allele was associated with increases in hippocampal formation (HF) and ventrolateral prefrontal cortex (VLPFC) activation during viewing of faces displaying negative emotion. The ability of COMT Met/Met subjects to focus attention on a set of stimuli and inhibit interference may have deleterious effects in environments requiring rapid and flexible processing. [unreadable] [unreadable] Our studies in patients with SCZ explored the integrity of brain structures underlying cognitive function and affective behavior. We examined the phenomenon of low activity and hyperactivity of the DLPFC in SCZ. Groups were subdivided on the basis of performance on the WM task into high or low performing subgroups. Results show that in high-performing SCZ there were locales of greater PFC activation as well as locales of less activation. While only locales of low PFC activation were found in the low performing patients. These findings suggest that SCZ whose performance on the N-back WM task is similar to that of healthy comparison subjects, but they use greater PFC resources and achieve lower accuracy (i.e., inefficiency). Other patients with SCZ fail to sustain the PFC network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in SCZ are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the DLPFC. [unreadable] [unreadable] The group also examined the effects of genetic variations on cognitive performance. One study found that healthy subjects with the COMT met/met and the DAT 10 repeat alleles had more focused WM response than those with COMT val and DAT 9 repeat alleles. This suggests, for the first time, an additive genetic effect of two DA regulating genes. As previously described, genetic variations of COMT impacts the level of PF dopamine. DA plays a critical role in determining the level of PF signal to noise during information processing. In our study, we found that genetic variation in the COMT gene may affect the efficiency by which DA is inactivated resulting in diminished BOLD fMRI response and increased noise in Val carriers. We also studied the impact of a genetic variation in MAOA and found that the low level variant increased risk for violent behavior and predicted structural and functional changes in the PF-amygdala-hippocampal system for emotional regulation.[unreadable] [unreadable] The group has also been exploring the effects of neuropharmacological manipulation on brain information processing. Evidence suggests that COMT may play a unique role in regulating DA flux in the PFC, the group explored if Tolcapone, a COMT inhibitor can improve efficiency in PFC function. Preliminary results from this study suggest that TOL does enhance the efficiency of PF cortical information processing, and add evidence that COMT plays a significant role in modulating DA tone in the PFC. In another study, using event-related fMRI, we examined the effects of oral dextroamphetamine treatment on brain activity and during active mental processing. We found that by enhancing tonic over phasic activation, dextroamphetamine treatment equalized levels of ventral striatal activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of dextroamphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses. [unreadable] [unreadable] The group also explored the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the neurophysiological correlates of reduced WM capacity with age we found that within WM capacity (as in 1-Back) when the elderly performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher WM loads (as in 2-Back and 3-Back), however, when they performed worse then the younger subjects, the elderly showed relatively reduced activity in these prefrontal regions. These data suggest that within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed beyond a threshold beyond which any compensation can be made probably from a failure to engage such compensatory mechanisms. This leads to a decline in performance. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.